tamoxifen

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tamoxifen

(təmŏk`sĭfĕn'), synthetic hormone used in the treatment of breast cancerbreast cancer,
cancer that originates in the breast. Breast cancer is the second leading cause of cancer death in women (following lung cancer). Although the vast majority of the cases occur in women, some men also get breast cancer.
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. Introduced in 1978, tamoxifen is used to prevent recurrences of cancer in women who have already undergone surgery to remove their tumors and to control metastatic breast cancer. In breast tissue, tamoxifen blocks the effect of estrogen on cancerous cells that need estrogen to grow; not all breast cancers are affected by tamoxifen and other selective estrogen receptor modulators. In postmenopausal women with breast cancer, aromatase inhibitors, which block the production of estrogen outside the ovaries, are typically used instead of tamoxifen. In 1998, a large study of healthy women at high risk for breast cancer showed that tamoxifen can also prevent first occurrence of the disease; women who took the drug had a 45% lower incidence of cancer that those who received a placebo, and tamoxifen is now also used to reduce the risk of breast cancer in high risk patients. Adverse effects include and increased risk of uterine and endometrial cancer, blood clots, stroke, and cataracts.
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1), in vivo analytical measurements of plasma samples from tamoxifen-treated patients have quantified few metabolites, including N-desmethyltamoxifen, endoxifen, 4-hydroxytamoxifen, N,N-didesmethyltamoxifen, [alpha]-hydroxytamoxifen, and tamoxifen-N-oxide (Table 1).
Finally, a series of laboratory studies for the characterization of its pharmacology established that endoxifen has a potency equivalent to 4-hydroxytamoxifen in terms of its binding affinity for ERs (16), suppression of estrogen-dependent proliferation of breast cancer cells (16, 89, 90), and modulation of estrogen-mediated global gene expression (91).
Lower metabolic ratios with respect to the formation of endoxifen and 4-hydroxytamoxifen but higher metabolic ratios for the formation of N-desmethyltamoxifen (endoxifen precursor) were observed in carriers of CYP2D6 variant genotypes, a result consistent with a gene-dosage effect.
10 homozygous variant and lower steady-state plasma concentrations of 4-hydroxytamoxifen and endoxifen (17), and a Chinese study found that patients homozygous for CYP2D6[sup.
Thus far, no study has addressed the question of whether genetically predisposed differences in 4-hydroxytamoxifen and endoxifen concentrations are associated with treatment response or disease progression and with side effects such as hot flashes, including phenocopying effects; therefore, therapeutic drug monitoring as a useful surrogate is currently not available in the case of tamoxifen.
Tamoxifen and the isomers of 4-hydroxytamoxifen in tamoxifen-resistant tumors from breast cancer patients.
Characterization of tamoxifen and 4-hydroxytamoxifen glucuronidation by human UGT1A4 variants.
DePinho's experiment did not suffer from an increased risk of cancer over the four-week course of their treatment with 4-hydroxytamoxifen, and inducing telomerase increased the median survival of these mice over that four-week period.